The long-term goal of this project is to provide information useful in predicting conditions in which non-target vertebrates may be unusually susceptible (or resistant) to the toxic action of pesticides, or of other chemicals as a result of exposure to pesticides. This will be accomplished by research directed at identifying, measuring and modifying the dynamic relationships among critical biochemical pathways of metabolism and action in relation to the response of intact organisms. In the proposed research, emphasis is placed on studies of interactions involving organophosphorus (OP) pesticides, primarily phosphorothionate insecticides. In this project year, laboratory animals (rats and mice) and their tissues will be treated with insecticides and analyzed in order to: (1) develop a more complete analytical program for measuring the total metabolism of Guthion and related organophosphates which will allow more definitive experiments to explain Guthion potentiation; (2) undertake structure potentiation studies in which the importance of the dithiophosphate, alkyl substituents and nature of the leaving groups on organophosphates will be evaluated with respect to potentiation by other organophosphates; (3) develop appropriate muscarinic agonist-receptor binding assays to characterize the nature of organophosphate-induced cholinergic tolerance and to determine if there are site-specific alterations in receptor kinetics or concentration; (4) develop appropriate assays for measuring enzymatic hydrolysis of phthalate esters and apply these to studies of the influence of esterase inhibitors on phthalate distribution; (5) further investigate the importance of route of exposure on the quality and degree of toxic interactions, organophosphate insecticides and substances which modify their metabolism.